Fibrous proteins, which serve a structural role in organisms, have a rodlike conformation composed of regular .alpha.-helical, triple helical, or .beta.-sheet/.beta.-turn secondary structure. The primary structure contains repeated sequences of amino acids. Fibrous proteins include fibroin, collagen, keratin, myosin, tropomyosin and fibrinogen.
Specialized fibrous proteins in insects constitute cocoon, web, and dragline silk. Silks are composed of cross-linked fibroin proteins whose structure is largely .beta.-sheet and .beta.-turn. Seven similar fibroin genes from spiders have been identified. By varying the pattern of expression of these different fibroins, spiders can produce silks of varying mechanical properties. The fibroin proteins have a pattern of alternating polyalanine or poly(glycinealanine) blocks and glycine-rich blocks. Hydrophobicity analysis shows a characteristic pattern of alternating hydrophobic and hydrophilic regions. (Guerette, P. A. et al. (1996) Science 272:112-115; and Hinman, M. et al. (1992) Results Probl. Cell Differ. 19:227-254.)
Collagen provides structure to bone, teeth, skin, ligaments, tendons, cartilage, blood vessels, and basement membranes. Multiple collagen proteins have been identified. Three collagen molecules fold together in a triple helix stabilized by interchain disulfide bonds. Bundles of these triple helices then associate to form fibrils. Collagen primary structure consists of hundreds of (Gly-X-Y) repeats where about a third (f the X and Y residues are Pro. Glycines are crucial to helix formation as the bulkier amino acid sidechains cannot fold into the triple helical conformation. Because of these strict sequence requirements, mutations in collagen genes have severe consequences. Osteogenesis imperfecta patients have brittle bones that fracture easily; in severe cases patients die in utero or at birth. Ehlers-Danlos syndrome patients have hyperelastic skin, hypermobile joints, and susceptibility to aortic and intestinal rupture. Chondrodysplasia patients have short stature and ocular disorders. Alport syndrome patients have hematuria, sensorineural deafness, and eye lens deformation. (Isselbacher, K. J. et al. (1994) Harrison's Principles of Internal Medicine, McGraw-Hill, Inc., New York, N.Y., pp. 2105-2117; and Creighton, T. E. (1984) Proteins, Structures and Molecular Principles, W.H. Freeman and Company, New York, N.Y., pp. 191-197.)
Keratin filaments, produced by epithelial cells, form the structural core of the outer layer of skin. This layer protects the dermis from desiccation and abrasion. Two keratin monomers dimerize to form an .alpha.-helical coiled coil. These coiled coil dimers associate in a series of steps to form filaments. The keratin primary structure shows a characteristic seven residue (heptad) repeat with hydrophobic residues predominating at positions 1 and 4. Mutations in keratin genes lead to epithelial diseases including epidermolysis bullosa simplex, bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis), non-epidermolytic and epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, pachyonychia congenita, and white sponge nevus. Some of these diseases result in severe skin blistering. (Lodish, H. et al. (1995) Molecular Cell Biology, Scientific American Books, New York, N.Y., pp. 1106-1116; Wawersik, M. et al. (1997) J. Biol. Chem. 272:32557-32565; and Corden L. D. and McLean, W. H. (1996) Exp. Dermatol. 5:297-307.)
In other disorders the pathology is derived from inappropriate deposition of fibrous proteins. Fibrocystic breast disease, whose cause is unknown. is characterized by breast pain, lumpiness, and cysts and may predispose women toward breast cancer. (Norwood, S. L. (1990) J. Obstet. Gynecol. Neonatal Nurs. 19:116-121.) Uterne fibroids, noncancerous growths of muscle and fibrous tissue in the wall of the uterus, occur in at least 20 percent of all women over age 35. Their cause is unknown, but estrogen levels appear to affect fibroid size. Fibroids may cause heavy or prolonged menstrual bleeding, anemia, infertility, miscarriage, early labor, and postpartum hemorrhage. (Berkow, R. et al. (1997) The Merck Manual of Medical Information Home Edition, Internet Edition, Section 22, Chapter 234.) Fibrosis of the penile corpora cavernosa in Peyronie's disease can cause impotence. (Isselbacher, supra, pp. 263-264.) Fibrosis in the palmar fascia (of the hand) in Dupuyten's contracture can cause loss of finger function. (Berkow, R. et al. (1992) The Merck Manual of Diagnosis and Therapy, Internet Edition, Section 10, Chapter 114, Tendinitis and Tenosynovitis, Dupuytren's Contracture.) Systemic sclerosis is characterized by fibrosis of the skin, blood vessels, gastrointestinal tract, lungs, heart, and kidneys. Patients suffer from skin thickening, pain, swelling, and stiffness of the fingers and knees, esophageal dysfunction, pulmonary hypertension, and renal failure, and there is no known cure. The cause is unknown but overproduction and accumulation of collagen and other extracellular matrix proteins are observed. (Isselbacher, supra, pp. 1655-1661.) Hepatic fibrosis occurs as a response to hepatocellular necrosis or injury; collagen accumulation leads to hepatic cell atrophy and disruption of hepatic blood flow. (Berkow, R. et al. (1992) The Merck Manual of Diagnosis and Therapy, Internet Edition, Section 6, Chapter 68, Fibrosis, Etiology, Pathogenesis.) Collagen is produced in two bone cancers, fibrosarcoma and malignant fibrous histiocytoma. (Cotran, R. S. et al. (1994) Robbins Pathologic Basis of Disease, W.B. Saunders Company, Philadelphia, Pa., p. 1243.)
The discovery of a new human fibrous protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of connective tissue disorders, reproductive disorders, cancer, and autoimmune/inflammatory disorders.